Glutamate is the major excitatory neurotransmitter in the central nervous system. AMPA receptors are one of three glutamate receptor ion channel subtypes identified, based on its sensitivity to the selective activator, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). AMPA receptors mediate cellular responses to glutamate by direct and indirect mechanisms. When activated by glutamate or AMPA, AMPA receptor ion channels allow sodium (Na+) and calcium ions (Ca2+) to pass directly through the channel pore.
Ion channel currents activated by glutamate via AMPA receptors are transient. The time course of currents is modified by refractory states caused during glutamate binding which is referred to as desensitization and by the rate of glutamate removal from the ion channel binding site which results in deactivation. Ion influx through AMPA receptors may be enhanced by compounds that either prevent desensitization or by compounds that slow deactivation rates. Compounds that enhance glutamate-stimulated ion influx at AMPA receptors are known as positive AMPA receptor allosteric modulators or AMPA receptor potentiators. Since AMPA receptors play a pivotal role in mediating fast excitatory transmission in the central nervous system, molecules that enhance AMPA receptor function have multiple therapeutic targets. Moreover, compounds that allosterically potentiate AMPA receptors have been shown to enhance synaptic activity in vitro and in vivo. Such compounds have also been shown to enhance learning and memory in rats, monkeys, and humans.
Several International Patent Application Publications, see WO 98/33496, WO 01/68592, and WO 01/90057, disclose certain sulfonamide derivatives useful, for example, as AMPA potentiators, and for treating a variety of disorders such as psychiatric and neurological disorders, and sexual dysfunction. There remains, however, a need for AMPA receptor potentiators that have increased potency and a greater margin of safety. The compounds of the Formula I may also be useful for improving memory (both short term and long term) and learning ability.